Brain Injury In Term Infants Research Articles

Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases

Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.

A Rare Cause of Epilepsy: Ulegyria Revisited in a Series of 10 Patients.

Introduction. Ulegyria results from perinatal hypoxic-ischemic brain injury in term infants. The specific mushroom-shaped configuration of ulegyria results from small atrophic circumvolutions at the bottom of a sulcus underlying an intact gyral apex. Clinically, ulegyria is generally associated with epilepsy. Here, we aimed to delineate the characteristics of patients with ulegyria and the epileptic seizures they experience. Material and methods. Medical records including radiology and pathology reports, video-electroencephalographic (EEG) analysis, operative notes, hospital progress and outpatient clinic notes were reviewed retrospectively in a total of 10 ulegyria patients. Results. Patients ages ranged between 24 and 58 years (mean, 32 ± 9.8 years). Past medical history was confirmed for neonatal asphyxia in 2 (20%). Neurological examination was remarkable for spastic hemiparesis in 1 (10%) patient with perisylvian ulegyria and for visual field deficits in 2 patients (20%) with occipital ulegyria. Ulegyria most commonly involved the temporoparietal region (n = 5, 50%) followed by the perisylvian area (n = 2, 20%). Except the one with bilateral perisylvian ulegyria, all patients had unilateral lesions (n = 9, 90%). Hippocampal sclerosis accompanied ulegyria in 2 patients (20%). All patients experienced epileptic seizures. Mean age at seizure onset was 8.8 ± 5.4 years (range, 2-20 years). Interictal scalp EEG and EEG-video monitoring records demonstrated temporoparietal and frontotemporal activities in 5 (50%) and 2 (20%) patients, respectively. The seizures were successfully controlled by antiepileptic medication in 8 patients (n = 8, 80%). The remaining 2 patients (%20) with concomitant hippocampal sclerosis required microsurgical resection of the seizure foci due to medically resistant seizures. Discussion. Ulegyria is easily recognized with its unique magnetic resonance imaging characteristics and clinical presentation in the majority of cases. It is highly associated with either medically resistant or medically controllable epileptic seizures. The treatment strategy depends on the age at onset and extends of the lesion that has a significant impact on the severity of the clinical picture.

Neuroprotective Effects of Diabetes Drugs for the Treatment of Neonatal Hypoxia-Ischemia Encephalopathy.

The perinatal period represents a time of great vulnerability for the developing brain. A variety of injuries can result in death or devastating injury causing profound neurocognitive deficits. Hypoxic-ischemic neonatal encephalopathy (HIE) remains the leading cause of brain injury in term infants during the perinatal period with limited options available to aid in recovery. It can result in long-term devastating consequences with neurologic complications varying from mild behavioral deficits to severe seizure, intellectual disability, and/or cerebral palsy in the newborn. Despite medical advances, the only viable option is therapeutic hypothermia which is classified as the gold standard but is not used, or may not be as effective in preterm cases, infection-associated cases or low resource settings. Therefore, alternatives or adjunct therapies are urgently needed. Ongoing research continues to advance our understanding of the mechanisms contributing to perinatal brain injury and identify new targets and treatments. Drugs used for the treatment of patients with type 2 diabetes mellitus (T2DM) have demonstrated neuroprotective properties and therapeutic efficacy from neurological sequelae following HIE insults in preclinical models, both alone, or in combination with induced hypothermia. In this short review, we have focused on recent findings on the use of diabetes drugs that provide a neuroprotective effect using in vitro and in vivo models of HIE that could be considered for clinical translation as a promising treatment.

The predictive accuracy of hypoxic scoring for prediction of adverse outcome in neonates born with asphyxia

Background: Birth asphyxia is a major contributor to neonatal mortality. Fetal hypoxia followed by asphyxia is common cause of brain injury in term infants. Hypoxia score has shown to be accurate enough to predict adverse outcome in asphyxiated neonates. But controversies exist regarding predictive accuracy of hypoxia score. So we conducted this study. Objective to assess the predictive accuracy of hypoxic scoring for prediction of adverse outcome in neonates born with asphyxia.Methods: 170 neonates were screed for hypoxia score. Neonates were labelled as positive or negative. Then all neonates were followed-up for 7 days. If neonate died within 7days, then case was confirmed as positive or negative. Data was analysed by using SPSS 20. 2x2 table was developed to calculate sensitivity, specificity, PPV, NPV and predictive accuracy of hypoxia score.Results: The mean Apgar score at birth was 5.01±0.83. The sensitivity of hypoxia score was 87.8%, specificity was 90.9%, PPV was 90%, NPV was 88.9% while predictive accuracy was 89.4% taking actual adverse outcome as gold standard.Conclusions: The predictive accuracy of hypoxia score was high for prediction of adverse outcome in asphyxiated neonates.

Protective role of microRNA-454-3p in neonatal hypoxic-ischaemic encephalopathy by targeting ST18

Hypoxic-ischaemic encephalopathy (HIE) resulting from perinatal asphyxia or intrapartum-related events is a common cause of neonatal brain damage death among neonatal brain injury and term infants. However, the potential mechanisms of brain injury in term infants with HIE remain to be elucidated. This study aimed to investigate the role of miR-454-3p in HIE. The protective effect of microRNA-454-3p (miR-454-3p) targeting ST18 on neonatal HIE was investigated by the HIE rat model and primary rat nerve cell oxygen and glucose deprivation (OGD) model. The expression of miR-454-3p was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell apoptosis and viability was detected by flow cytometry and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, respectively. TargetScan predicted the binding sites between miR-454-3p and ST18. Dual luciferase reporter system was used to validate the relationship between ST18 and miR-454-3p. We found a significant decrease in miR-454-3p expression in the brain tissue of rats with HIE, while apoptosis and S100B and neuron-specific enolase (NSE) expression were significantly increased. In addition, miR-454-3p was significantly decreased in OGD-induced neurons, while the mRNA and protein expression of ST18 was significantly increased. OGD reduced neuronal cell viability and increased cell apoptosis were significantly inhibited by miR-454-3p mimic, but all these effects were significantly reversed by over-expression of ST18 gene. In conclusion, our study suggested that miR-454-3p was down-regulated in HIE rats, and it could attenuate OGD-induced neuronal apoptosis by targeting ST18, thereby playing a protective role in HIE, which might become a new and effective therapeutic target for HIE.

High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial – Background, Aims, and Study Protocol

Background: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. Results and Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis

In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and childhood disability. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. While studies show CHORIO contributes to preterm CNS injury and is also a common independent risk factor for brain injury in term infants, the molecular mechanisms mediating inflammation in the placental-fetal-brain axis that result in PBI remain a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been clinically implicated in CHORIO and in mature CNS injury, although their specific role in PBI pathophysiology is poorly defined. Given CXCL1/CXCR2 signaling is essential to neural cell development and neutrophil recruitment, a key pathological hallmark of CHORIO, we hypothesized CHORIO would upregulate CXCL1/CXCR2 expression in the placenta and fetal circulation, concomitant with increased CXCL1/CXCR2 signaling in the developing brain, immune cell activation, neutrophilia, and microstructural PBI. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague Dawley rats to induce CHORIO. Specifically, uterine arteries were occluded for 60min to induce placental transient systemic hypoxia-ischemia (TSHI), followed by intra-amniotic injection of lipopolysaccharide (LPS). Pups were born at E22. Placentae, serum and brain were collected along an extended time course from E19 to postnatal day (P)15 and analyzed using multiplex electrochemiluminescence (MECI), Western blot, qPCR, flow cytometry (FC) and diffusion tensor imaging (DTI). Results demonstrate that compared to sham, CHORIO increases placental CXCL1 and CXCR2 mRNA levels, concomitant with increased CXCR2+ neutrophils. Interestingly, pup serum CXCL1 expression in CHORIO parallels this increase, with sustained elevation through P15. Analyses of CHORIO brains reveal similarly increased CXCL1/CXCR2 expression through P7, together with increased neutrophilia, microgliosis and peripheral macrophages. Similar to the placenta, cerebral neutrophilia was defined by increased CXCR2 surface expression and elevated myeloperoxidase expression (MPO), consistent with immune cell activation. Evaluation of microstructural brain injury at P15 with DTI reveals aberrant microstructural integrity in the callosal and capsular white matter, with reduced fractional anisotropy in superficial and deep layers of overlying cortex. In summary, using an established model of CHORIO that exhibits mature CNS deficits mimicking those of preterm survivors, we show CHORIO induces injury throughout the placental-fetal-brain axis with a CXCL1/CXCR2 inflammatory signature, neutrophilia, and microstructural abnormalities. These data are concomitant with abnormal cerebral CXCL1/CXCR2 expression, and support temporal aberrations in CXCL1/CXCR2 and neutrophil dynamics in the placental-fetal-brain axis following CHORIO. These investigations define novel targets for directed therapies for infants at high risk for PBI.

Primary outcome of babies with hypoxic ischemic encephalopathy

Background: Intrapartum fetal hypoxia followed by hypoxic ischemic encephalopathy (HIE) is a common cause of potentially avoidable brain injury in term infants. This study was conducted in a tertiary care centre and included 119 babies of hypoxic ischemic encephalopathy born in hospital as well as referred from neighbouring areas. Methods: Babies with history of intrapartum hypoxia, delayed cry who required resuscitation at birth and in stage II or III of modified sarnat encephalopathy grade (MSEG) and those who had abnormal intrapartum course were included. After performing clinical neurological assessment further data collection included perinatal maternal characteristics- ante partum and intrapartum complications; morbidity pattern in baby including type of resuscitation, onset of seizure, antiepileptic drug, other co morbidity and short term outcome. Results: Out of 119 babies 19% were born low birth and 6% were IUGR. 47% mother were primi gravida whereas 53% were multigravida, 32% pregnancy were unbooked. Ante partum risk factor was found in 3 cases and Intrapartum risk factor was found in 45 (38%) cases. According to MSEG stage II and III babies were enrolled overall 92% babies had seizure and 60% had on day one only. Single antiepileptic drug controlled seizure in 60% of babies who had seizure additional two and more antiepileptic drug were required in fewer no of cases. During stay most common complication was sepsis, observed in 26% cases followed by DIC in 11% cases and AKI in 7% cases. Majority 59% of babies were discharged, mortality was observed in 12.6% cases and 27% left against medical advice. Conclusions: Maternal perinatal risk factors and effective neonatal intervention may improve outcome in babies with hypoxic ischemic encephalopathy.

577: Diffusion imaging to detect brain injury in term infants

577: Diffusion imaging to detect brain injury in term infants

7: EFM and peripartum factors associated with brain injury in term infants

7: EFM and peripartum factors associated with brain injury in term infants

MRI brain imaging in neonates

Abstract MRI is now commonly used in the assessment of neonates for diagnosis and prognosis. The advantages over ultrasound are increased contrast resolution, complete coverage and multiplanar imaging. MRI is most commonly used for the assessment of neonatal encephalopathy to determine an underlying cause such as hypoglycaemia, neonatal infarction, or viral encephalitis, and may also be useful in determining complications of meningitis and planning surgical treatment. In hypoxic-ischaemic injury, where the diagnosis is typically made clinically, MRI has conventionally confirmed the diagnosis and provided prognostic information. However advanced techniques such as magnetic resonance spectroscopy and arterial spin labelling allow for earlier diagnosis and may guide treatment options. MRI may also detect less common patterns of brain injury in term infants such as punctuate white matter lesion. Imaging of preterm infants at term equivalent age can demonstrate complications such as periventricular leucomalacia or periventricular haemorrhagic infarction and provide information on neurological outcome.

Changing Pattern of Perinatal Brain Injury in Term Infants in Recent Years

Perinatal brain injury in term infants remains a significant clinical problem. Recently a change appears to have occurred in the pattern of such injuries. We sought to characterize the incidence, etiology, clinical manifestations, and outcomes of these injuries. A retrospective chart review identified clinical characteristics of neuroimaging, electroencephalography, and placental pathologic findings. Perinatal depression was defined as hypotonia and the need for respiratory support. From January 2004-December 2009, 29,597 term deliveries occurred. Brain injuries in 33 infants (live term births) included hypoxic-ischemic encephalopathy (n = 8; 0.27/1000), subdural hemorrhage (n = 10; 0.34/1000), intraventricular/intraparenchymal hemorrhage (n = 5; 0.17/1000), and focal cerebral infarctions (n = 4; 0.14/1000). Thirteen of 33 infants (39%) were triaged to a regular nursery. Delayed presentations included apnea (n = 6), desaturation episodes (n = 3), and seizures (n = 4). Twenty of 33 (61%) were admitted directly to the neonatal intensive care unit because of perinatal depression or evolving hypoxic-ischemic encephalopathy. Clinical signs included seizures (n = 12) and apnea (n = 2). Nine of 19 manifested electroencephalographic seizures. Pathology included chorioamnionitis (n = 7) and fetal thrombotic vasculopathy (n = 5). The latter was associated with focal cerebral infarctions in 3/4 cases. Most cases attributable to perinatal brain injury, except for evolving hypoxic-ischemic encephalopathy, are not identified according to any perinatal characteristics until the onset of signs, limiting opportunities for prevention.

The Asphyxiated Neonatal Thalamus: A Diffusion Tensor Imaging Study

Background and Aims: Perinatal asphyxia is an important cause of permanent brain injury in term infants. An important neuroimaging indicator of neurodevelopmental prognosis following perinatal asphyxia is the extent of thalamic involvement. However the different patterns of injury seen within thalamus remain unclear. We used diffusion tensor imaging to study these patterns.Methods: In this retrospective study, we analysed DTI scans of 24 patients diagnosed with perinatal asphyxia, scanned between day 4-7 after birth. Images were acquired using a GE 1.5 Tesla system. Regions of interest were manually placed in four different thalamic regions (ventrolateral, medial, anterior and posterior region) and four localisations in cortex (prefrontal, parietal (post S1), occipital and temporal). ADC values were calculated using ‘DTI-studio’. Pearson's correlation coefficient and a multiple regression analysis were used (SPSS 17.0) to study relations between cortical and thalamic values.Results: We found significant correlations between prefrontal cortical ADC values and (connected) anterior- and medial thalamic regions. Temporal ADC values were correlated to Posterior thalamic regions. Occipital and parietal cortex showed highest correlation with posterior thalamic regions.Conclusions: Our study reveals significant correlations between the decrease of ADC values of thalamic nuclei and their anatomically corresponding cortical areas in perinatal asphyxia. These findings help explain different injury patterns seen within the asphyxiated thalamus. Unravelling these thalamic injury patterns using DTI could provide insights needed to improve our prognostication following perinatal asphyxia.

Iron Overload in Very Low Birth Weight Infants: Serum Ferritin and Adverse Outcomes

Adequate iron isessential for growth and haematpoiesis. Oral iron supplementation is the standard of care in VLBW infants. Post mortem evidence has confirmed significant iron overload. Excessive free iron has been associated with free radical formation and brain injury in term infants. Iron indices were measured in VLBW infants (weight 300microg/L was considered elevated. Data was analysed using SPSS Version 14.0. Associations were assessed using Mann Whitney U tests for non-parametric variables and p< 0.05. Ferritin levels were elevated in 31% (n=14). The mean ferritin level was 270microgms/L. The mean total Iron was within normal limits at 16.64umol (11-34umol). However mean Transferrin and TIBC levels were below normal at 1.75g/dl (2-3g/dl) and 42.35umol (50-85umol) respectively. 19 MRIs had been conducted at term. Of 6 MRIs conducted in the high ferritin group, 3 were abnormal and 3 were normal. In the low ferritin group 13 MRIS were conducted at term, 10 were normal and 3 were abnormal. In this group of healthy VLBW infants there was a 31% of iron overload at time of starting routine iron supplementation. ELBW and lower gestational age were risk factors for developing iron overload which seems to be associated with number of transfusions required. VLBW infants with high ferritin longer on both NCPAP and 02.

Current Management of the Infant Who Presents with Neonatal Encephalopathy

Neonatal encephalopathy after perinatal hypoxic-ischemic insult is a major contributor to global child mortality and morbidity. Brain injury in term infants in response to hypoxic-ischemic insult is a complex process evolving over hours to days, which provides a unique window of opportunity for neuroprotective treatment interventions. Advances in neuroimaging, brain monitoring techniques, and tissue biomarkers have improved the ability to diagnose, monitor, and care for newborn infants with neonatal encephalopathy as well as predict their outcome. However, challenges remain in early identification of infants at risk for neonatal encephalopathy, determination of timing and extent of hypoxic-ischemic brain injury, as well as optimal management and treatment duration. Therapeutic hypothermia is the most promising neuroprotective intervention to date for infants with moderate to severe neonatal encephalopathy after perinatal asphyxia and has currently been incorporated in many neonatal intensive care units in developed countries. However, only 1 in 6 babies with encephalopathy will benefit from hypothermia therapy; many infants still develop significant adverse outcomes. To enhance the outcome, specific diagnostic predictors are needed to identify patients likely to benefit from hypothermia treatment. Studies are needed to determine the efficacy of combined therapeutic strategies with hypothermia therapy to achieve maximal neuroprotective effect. This review focuses on important concepts in the pathophysiology, diagnosis, and management of infants with neonatal encephalopathy due to perinatal asphyxia, including an overview of recently introduced novel therapies.

Treating Neonatal Brain Injury - Promise and Inherent Research Challenges

In this review we discuss current challenges faced by researchers and clinician-scientists in the pursuit of therapeutics to treat hypoxic-ischemic (HI) brain injury in term infants. At present, there is an absence of neuroprotective drugs that are safe and effective for the protection of neonates from neurological sequels after HI. We discuss secondary neurotoxic processes elicited by HI that may be targets for therapeutic interventions with a specific focus on inflammatory mechanisms. Advances in research to unravel these cellular processes and molecular mechanisms that drive injurious processes after HI have traditionally been plagued by conflicting results when assessing different times for intervention, different models for brain injury, and the adult versus neonate brain. We attribute impeded drug development in part to such disparate results and general difficulties to conduct a stringent, comprehensive analysis of candidate drugs prior to clinical trials. It will be imperative to implement changes in the clinic and laboratory in order for future drug initiatives to achieve success. We also provide a brief discussion on the pursuit of anti-inflammatory molecules and monitoring methods that are the focus of current patents and that, in our opinion, may lead to important new developments in the treatment of HI brain injury in newborn infants.

Patterns of Brain Injury in Term Neonatal Encephalopathy

Neonatal encephalopathy remains a major cause of neurologic and developmental disability in term infants. Approximately one in 5 affected infants die during the neonatal period, and another one fourth have permanent motoror cognitive dysfunction. Previous studies suggest that brain injury occurs at-or near-the time of birth and so might be helped by postnatal interventions. The investigators used magnetic resonance imaging (MRI) to define patterns of injury in 173 term newborn infants having neonatal encephalopathy. MRI was done 1 to 24 days after birth, the median interval being 6 days. MRI distinguished between a watershed-predominant pattern (involving white matter, especially in the vascular watershed and possibly extending to cortical gray matter); a basal ganglia/thalamus-predominant pattern (involving the deep gray nuclei and perirolandic cortex, extending to the total cortex in severe cases); and a normal state. Neuroradiologists without knowledge of the clinical findings interpreted the MRI scans. Cognitive development was assessed by the Mental Development Index of the Bayley Scales of Infant Development II. The watershed pattern of injury was found in 45% of infants and the basal ganglia/thalamus pattern in 25%; 30% had normal MRI findings. Injury patterns could not be related to maternal substance use, gestational diabetes, premature rupture of membranes, preeclampsia, or intrauterine growth restriction. The basal ganglia/thalamus pattern of injury was associated with more severe clinical signs, more intensive resuscitation at birth, more advanced encephalopathy, and more severe seizures. This pattern also correlated with the most marked impairment of motor and cognitive outcomes at age 30 months. No newborn infant with normal MRI findings had a functional motor deficit. More than half (56%) of surviving infants with the basal ganglia/thalamus pattern had spastic quadriparesis. Additional watershed injury did not worsen neuromotor scores when the basal ganglia/thalamus-predominant pattern was observed. Neuromotor scores did not change from ages 12 to 30 months. These findings show that different patterns of brain injury in term infants with neonatal encephalopathy are associated with different neurodevelopmental outcomes. Knowledge of the pattern of injury can help to identify infants who might benefit most from measures that protect the brain after injury as well as those who may benefit from rehabilitative services.

Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia.

To determine the potential contribution of initial hypoglycemia to the development of neonatal brain injury in term infants with severe fetal acidemia. A retrospective chart review was conducted of 185 term infants who were admitted to the neonatal intensive care unit between January 1993 and December 2002 with an umbilical arterial pH <7.00. Short-term neurologic outcome measures include death as a consequence of severe encephalopathy and evidence of moderate to severe encephalopathy with or without seizures. Hypoglycemia was defined as an initial blood glucose < or =40 mg/dL. Forty-one (22%) infants developed an abnormal neurologic outcome, including 14 (34%) with severe hypoxic ischemic encephalopathy who died, 24 (59%) with moderate to severe hypoxic ischemic encephalopathy, and 3 (7%) with seizures. Twenty-seven (14.5%) of the 185 infants had an initial blood sugar < or =40 mg/dL. Fifteen (56%) of 27 infants with a blood sugar < or =40 mg/dL versus 26 (16%) of 158 infants with a blood sugar >40 mg/dL had an abnormal neurologic outcome (odds ratio [OR]: 6.3; 95% confidence interval [CI]: 2.6-15.3). Infants with abnormal outcomes and a blood sugar < or =40 mg/dL versus >40 mg/dL had a higher pH (6.86 +/- 0.07 vs 6.75 +/- 0.09), a lesser base deficit (-19 +/- 4 vs -23.8 +/- 4 mEq/L), and lower mean arterial blood pressure (34 +/- 10 vs 45 +/- 14 mm Hg), respectively. There was no difference between groups in the proportion of infants who required cardiopulmonary resuscitation (7 [46%] vs 15 [57%]) and those with a 5-minute Apgar score <5 (11 [73%] vs 22 [85%]). By multivariate logistic analysis, 4 variables were significantly associated with abnormal outcome: initial blood glucose < or =40 mg/dL versus >40 mg/dL (OR: 18.5; 95% CI: 3.1-111.9), cord arterial pH < or =6.90 versus >6.90 (OR: 9.8; 95% CI: 2.1-44.7), a 5-minute Apgar score < or =5 versus >5 (OR: 6.4; 95% CI: 1.7-24.5), and the requirement for intubation with or without cardiopulmonary resuscitation versus neither (OR: 4.7; 95% CI: 1.2-17.9). Initial hypoglycemia is an important risk factor for perinatal brain injury, particularly in depressed term infants who require resuscitation and have severe fetal acidemia. It remains unclear, however, whether earlier detection of hypoglycemia, such as in the delivery room, in this population could modify subsequent neurologic outcome.

Seizure-Associated Brain Injury in Perinatal Asphyxia

Brain injury in term infants with neonatal asphyxia and seizures was evaluated by MRI and MRS at the University of California, San Francisco.

Models of white matter injury: Comparison of infectious, hypoxic‐ischemic, and excitotoxic insults

White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1-7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored.